3-(substituted amino)-1h-isoindoles

ABSTRACT

3-(Substituted or unsubstituted amino)-1H-isoindoles, prepared by condensing 3-alkoxy-1H-isoindoles or 3-(chloro or bromo)-1Hisoindoles with amine derivatives and optionally acylating the resulting 3-(primary or secondary amino)-1H-isoindoles or condensing the resulting 3-hydrazino-1H-isoindoles with an aldehyde or a ketone, are useful as antibacterial agents and as antihypertensive agents.

IJnited States Patent 91 Diana [54] S-(SUBSTITUTED AMINO)-1H- ISOINDOLES [75] Inventor: Guy I). Diana, Stephentown, N.Y.

[73] Assignee: Sterling Drug Inc., New York, N.Y.

[22] Filed: Aug. 10, 1970 [21] Appl. No.: 62,701

[52] U.S. Cl. ..260/240 F, 424/274, 260/240 G,

260/325, 260/326.1, 260/566 A [51] Int. Cl. ..C07d 27/48 [58] Field of Search ..260/240 F, 326.1

[56] References Cited OTHER PUBLICATIONS Sieveking et al., Angew. Chem. Int. Ed. Engl. 1969, Vol. 8, pages 457-458 (published June 1969). i

[ 1 3,723,421 Mar. 27, 1973 Bartlett et al., J. Chem. Soc., Section C., Organic, 1969, pages 129 to 133.

Primary ExaminerJohn D. Randolph Att0rneyElmer J. Lawson, B. Woodrow Wyatt, Thomas L. Johnson, Robert K. Bair, William G. Webb and Frederik W. Stonner [57] ABSTRACT 20 Claims, N0 Drawings 3-(SUBSTKTUTEI) AMINO)- lH-ISOINDOLES NEW COMPOSITIONS OF MATTER AND PROCESSES This invention relates to new and useful compositions of matter classified in the art of chemistry as isoindoles and to processes for their preparation.

In its composition of matter aspect my invention pro vides 1-(X)-1-(X )-3-(Y)-5-(Z)-6-(Z')1H-isoindole of the formula Y (Formula I) wherein X, when taken alone, is hydrogen, atertiary alkyl of one to four carbon atoms, phenyl, or phenylalkyl of seven to ten carbon atoms;

X, when taken alone, is hydrogen;

X and X, when taken together, are benzylidene, a-

chlorobenzyl-idene, or a-bromobenzylidene;

wherein Q, when taken alone, is hydrogen; alkyl of one to six carbon atoms; phenylalkyl of seven to ten carbon atoms; (CH ),,-T, wherein n is two or three and T is dialkylamino, wherein alkyl of dialkylamino is atertiary alkyl of one to four carbon atoms; alkanoyl of one to six carbon atoms; benzoyl; phenylalkanoyl of eight to eleven carbon atoms; amino or hydroxy;

Q, when taken alone, is hydrogen or atertiary alkyl of one to four carbon atoms;

and Q, when taken together with N, are l-azacycloalkyl of five to seven ring atoms and four to ten carbon atoms;

R, when taken alone, is hydrogen, alkyl of one to six carbon atoms, alkeny] of two to six carbon atoms, cycloalkyl 'of three to seven ring atoms and three to ten carbon atoms, cycloalkenyl of five to seven ring atoms and five to ten carbon atoms, phenyl, phenylalkyl of seven to ten carbon atoms or phenylalkenyl of eight to ten carbon atoms;

R, when taken alone, is hydrogen or atertiary alkyl of one to four carbon atoms;

R and R, when together with C, are cycloalkylidene of five to seven ring atoms and five to ten carbon atoms;

Z and Z, when taken alone, are the same or different and are hydrogen, atertiary alkyl of one to four carbon atoms, halo, hydroxy or atertiary alkoxy of one to four carbon atoms;

Z and Z, when taken together, are methylenedioxy;

and wherein, when X and X, when taken together,

are benzylidene,

a-chlorobenzylidene, or a-bromobenzylidene; when Q is phenylalkyl of seven to ten carbon atoms or benzoyl and when R is phenyl; the benzene ring thereof can be substituted by one to three members selected from the group consisting of halo, hydroxy, atertiary alkyl of one to four carbon atoms, atertiary alkoxy of one to four carbon atoms and phenylalkoxy of seven to ten carbon atoms or by a member selected from the group consisting of atertiary alkylthio of one to four carbon atoms, dialkylamino and B-dialkylarninoethoxy, wherein alkyl of dialkylamino is atertiary alkyl of one to four carbon atoms, ni'tro and sulfamoyl;

and acid addition salts thereof.

The isoindoles of Formula I and acid addition salts thereof have antibacterial activity and antihypertensive activity and are useful as antibacterial agents and as antihypertensive agents.

In one of its process aspects my invention provides the process for producing l-(X)-l-(X)-3-(NQQ")- 5-(Z)-6-(Z l H-isoindole of the formula wherein X", when taken alone, is hydrogen, atertiary alkyl of one to four carbon atoms, phenyl, or phenylalkyl of seven to ten carbon atoms;

X, when taken alone, is hydrogen as recited above for Formula I;

X and X, when taken together, are benzylidene or benzylidene substituted in the benzene ring as recited above for Formula I;

Q, when taken alone, is hydrogen or atertiary alkyl of one to four carbon atoms as recited above for Formula I; I

Q, when taken alone, is hydrogen; alkyl of one to six carbon atoms; phenylalkyl of seven to ten carbon atoms; (CI-I ),,-T, wherein n is two or three and T is dialkylamino, wherein alkyl of dialkylamino is atertiary alkyl of one to four carbon atoms; amino or hydroxy;

Q and Q", when taken together with N, are l-azacycloalkyl of five to seven ring atoms and four to ten carbon atoms;

Z and Z are defined as recited above for Formula I;

which comprises the step of condensing l-(X)-l- (X)-3-(OQ)-5-(Z)-6-(Z) ll-I-isoindole of the formula XII Z! x! Z ()Q' (Formula III) wherein the formula XII! Q Q (Formula IV) wherein X is phenyl or phenyl substituted as recited above for Formula I;

X" is chloro or bromo;

Q and Q" are defined as recited above for Formula II; and Z and Z are defined as recited above for Formula I; which comprises the steps of chlorinating or brominating 3-(X-methylene)-5-(Z')-6- (Z)-phthalimidine of the formula H XIII Formula V) and condensing the resulting l-(X"',X""-methylene)- 3-(X' )-5-(Z)-6-(Z )-lI-I-isoindole of the formula X" (Formula VI) with an amine, a hydrazine or a hydroxylamine of the formula HNQ'Q".

In still another of its process aspects my invention provides the process for producing l-(X)-l-(X')-3- (NQQ )-5-(Z)-6-(Z' l I-I-isoindole ofthe formula ILQQW (Formula VII) wherein X and X are defined as recited above for Formula I;

Q is hydrogen or atertiary alkyl of one to four carbon atoms as recited above for Formula I;

Q" is alkanoyl of one to six carbon atoms, benzoyl, phenyl-alkanoyl of eight to eleven carbon atoms or benzoyl substituted in the benzene ring as recited above for Formula I; and

Z and Z' are defined as recited above for Formula I; which comprises the step of acylating l-(X)-l-(X' )-3-(NHQ')-5-(Z)-6-(Z')-1H-isoindole of the forwith an acyl chloride of the formula Q""Cl, an acyl bromide of the formula Q""Br or an acid anhydride of the formula (Q"") O.

In yet another of its process aspects my invention provides the process for producing l-(X)-l-(X)-3- (NHN=CRR')-5-(Z)-6-(Z')-lI-I-isoindole of the formula Formula (VIII) NHN=CRR (Formula IX) wherein X, X, R, R, -Z and Z are defined as recited above for Formula I, which comprises the step of condensing l-(X)-1-(X)-5-(Z)-6-(Z')-3-hydrazino-lH- isoindole of the formula X Z I- z P IHNHz (Formula X) with an aldehyde or ketone of the formula O=CRR'.

Throughout this specification a symbol used in one formula has the same meaning when used in any other formula.

In the definitions of the formulas above atertiary alkyl of one to four carbon atoms is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl. Atertiary alkoxy of one to four carbon atoms is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or sec-butoxy. Atertiary alkylthio of one to four carbon atoms is methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio or sec-butylthio.

When X, Q, Q" or R is phenylalkyl of seven to ten carbon atoms, phenylalkyl is, for example, benzyl, lphenylethyl, 3-phenylpropyl or l-methyI-l-phenylethyl.

When Q, Q or R is alkyl of one to six carbon atoms, alkyl can be branched or unbranched alkyl, as illustrated by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

When Q or Q" is alkanoyl of one to six carbon atoms, alkanoyl is, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivalyl or caproyl.

When Q or Q"" is phenylalkanoyl of eight to eleven carbon atoms, phenylalkanoyl is, for example, phenylacetyl, B-phenylpropionyl or B-phenylbutyryl.

When Q and Q, taken together with N, are l-azacyclo-alkyl of five to seven ring atoms and four to ten carbon atoms, l-azacycloalkyl can be branched or unbranched l-azacycloalkyl, as illustrated by l-pyrrolidinyl, piperidino, 4-methyl-l-piperidinyl and l-hexahydroazepinyl.

When R is alkenyl of two to six carbon atoms, alkenyl can be branched or unbranched alkenyl, as illustrated by vinyl, allyl, l-methyl-l-propenyl and 2-hexenyl.

When R is cycloalkyl of three to seven ring atoms and three to ten carbon atoms, cycloalkyl can be branched or unbranched cycloalkyl, as illustrated by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4- methylcyclohexyl and cycloheptyl.

When R is cycloalkenyl of five to seven ring atoms and five to ten carbon atoms, cycloalkenyl can be branched or unbranched cycloalkenyl, as illustrated by l-cyclopentenyl, 3-cyclohexenyl, 4-methyl-3-cyclohexenyl and l-cycloheptenyl.

When R is phenylalkenyl of eight to ten carbon atoms, phenylalkenyl is, for example, styryl, a-methylstyryl or B-methylstyryl.

When R and R, taken together with C, are cycloalkylidene of five to seven ring atoms and five to ten carbon atoms, cycloalkylidene can be branched or unbranched cycloalkylidene, as illustrated by cyclopentylidene, cyclohexylidene, 4-methylcyclohexylidene and cycloheptylidene.

As benzene ring substituents halo is fluoro, chloro, bromo or iodo and phenylalkoxy is illustrated by benzyloxy, B-phenylethoxy and B-phenylpropoxy.

The manner and process of making and using the invention and the best mode of carrying it out will now be described so as to enable any person skilled in the art to which it pertains to make and use it.

Condensation of l-(X")-l-(X)-3-(OQ")-5-(Z)-6- (Z')-ll-I-isoindole of Formula III with an amine, a hydrazine or a hydroxylamine of the formula HNQ'Q' or an acid addition salt thereof is performed with or without a diluent at a temperature in the range of -150C. lf a diluent is used, it can be any solvent inert under the reaction conditions, for example, methanol, ethanol, 2-propanol, acetonitrile, dimethylsulfoxide, N,N-dimethylformamide or mixtures thereof.

Chlorination or bromination of l-(X"-methylene)- -(Z)-6-(Z')-phthalimidine of Formula V is accomplished using a chlorinating or brominating agent, preferably thionyl chloride or thionyl bromide, with or without a diluent at a temperature in the range of 0l 50C. If a diluent is used, it can be any solvent inert under the reaction conditions, for example, chloroform, benzene or chlorobenzene.

Condensation of l-(X", X""-methylene)-3-(X")- 5-(Z)-6-(Z)-lH-isoindole of Formula VI with an amine, a hydrazine or a hydroxylamine of the formula l-INQQ" is carried out using a solvent inert under the reaction conditions at a temperature in the range of 0- 150C. Ether is the preferred solvent, although tetrahydrofuran, chloroform, benzene or dioxane or mixtures thereof can also be used.

Acylation of l-(X)-l-(X)-3-(NHQ')-5-(Z)-6-(Z')-l l-l-isoindole of Formula VIII with an acyl chloride of the formula Q""Cl, an acyl bromide of the formula Q""Br or an acid anhydride of the formula (Q"") O is done using a solvent inert under the reaction conditions, for example, tetrahydrofuran, chloroform, benzene, dioxane, pyridine, N,N-dimethylformamide or mixtures thereof and an acid acceptor, for example, triethylamine or pyridine, at a temperature in the range of 0l 50C.

Condensation of l-(X)-l-(X')-5-(Z)-6-(Z')-3- hydrazinol H-isoindole of Formula X with an aldehyde or a ketone of the formula O=CRR' is effected with or without a diluent at a temperature in the range of Ol 50C. If a diluent is used it can be any solvent inert under the reaction conditions, for example, methanol, ethanol, ether, benzene, tetrahydrofuran or mixtures thereof.

Acid addition salts of the isoindoles of Formula I of my invention can be prepared with any pharmaceutically acceptable inorganic (mineral) or organic acid.If inorganic, the acid can be, for example, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, or sulfamic acid. If organic, the acid can be, for example, acetic acid, glycolic acid, lactic acid, quinic acid, hydrocinnamic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, cyclohexanesulfarnic acid or picric acid.

For the pharmaceutical purposes of this invention the free base forms of the isoindoles of Formula I and their corresponding acid addition salts are considered to be equivalent. That the protonic acid be pharmaceutically acceptable means that the beneficial properties inherent in the free base not be vitiated by side effects ascribable to the anions.

Although pharmaceutically acceptable salts are preferred, all acid addition salts are within the scope of the invention. A pharmaceutically unacceptable salt may be useful, for example, for purposes of identification or purification or in preparing a pharmaceutically acceptable salt by ion exchange procedures.

When crystalline, the isoindoles of Formulas I-X and their acid addition salts are purified by recrystallization and are characterized by their melting points (m.p.). When liquid, the isoindoles of Formulas I-XI are purified by distillation under reduced pressure and are characterized by their boiling points (b.p./mm.I-Ig.). The structures of the isoindoles of Formula I follow from the route of synthesis and are corroborated by infrared spectral analysis, by nuclear magnetic resonance spectral analysis and by the correspondence of calculated and found values of elemental analysis of representative samples.

As stated above the isoindoles of Formula I have antibacterial activity. This activity was measured by two test methods.

The first method is the spot plate test, which involves placing a few crystals of the compound to be tested on a seeded agar plate, incubating the plate and examining the plate for zones of inhibition of bacterial growth. A compound producing a zone of inhibition is recorded as active and a compound producing no zone of inhibition as inactive.

The second method is the broth dilution test by the Autotiter method. To the first cup of the Autotray is added an aliquot (0.08 ml.) of an aqueous solution 1,000 mcg./ml.) of the compound to be tested. Activation of the Autotiter initiates a sequence of operations in which an aliquot (0.05 ml.) of the solution in the first cup is withdrawn by a Microtiter transfer loop and diluted in sterile tryptose phosphate broth (0.05 ml.) in the second cup. Inoculated tryptose phosphate broth (0.05 ml.) containing triphenyltetrazolium chloride (50 mcg./ml.) as an indicator is then automatically added. After the initial dilution, the dilutions continue in two-fold decrements (from 250 to 0.06 mcg./ml.). The Autotray is incubated (18-20 hr. at 37C.) and the minimum inhibitory concentration determined as the concentration which inhibits formation of a red precipitate of the indicator. The isoindoles of Formula I had minimum inhibitory concentrations in the range of 15-250 micrograms per milliliter in this test.

In a modification of the foregoing broth dilution test the initial aliquot is different (0.1 mcg./ml. instead of 0.08 meg/ml), the broth contains glucose instead of tryptose phosphate, no indicator is used, the dilution range is difierent (from 500 to 0.06 mcg./ml. instead of 250 to 0.06 mcg./ml.) and inhibition is judged by turbidity instead of by the appearance of a red precipitate.

The organisms used in the two broth dilution tests were Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Proteus vulgaris.

As stated above the isoindoles of Formula I also have antihypertensive activity, which was detennined in unanesthetized renal hypertensive rats using the photoelectric tensometer foot method described by Kersten, Brosene, Ablondi and SubbaRow, Journal of Laboratory and Clinical Medicine 32, 1090 (1947). In this test the compound to be tested is administered orally, preferably in the form of a pharmaceutically acceptable acid addition salt, as a solution or suspension in distilled water, by stomach tube with the aid of l percent gum tragacanth or subcutaneously to groups of three renal hypertensive rats at each of four different dose levels graduated at 0.3 to 0.9 logarithmic intervals. The systolic blood pressure is determined for each of the three rats at each dose level before medication and at intervals of l, 2, 4, 5, 24 and 48 hours after medication. The unmedicated rats are considered hypertensive if the systolic blood pressure is 160 millimeters of mercury or greater. The medicated rats are considered normotensive if the systolic blood pressure is 130 millimeters of mercury or less. Each blood pres sure reading is judged by these criteria. The dose level of test compound which reduces the systolic blood pressure to a normotensive level in 50 percent of the animals is defined as the AED (approximate effective dose) value. When tested in this way, the isoindoles of Formula I were found to have AED values in the range of -50 milligrams per kilogram.

The preparation of the intermediates of Formulas Ill and V will now be described.

Alkylation of 3-(X")-3-(X')-5-(Z')-6-(Z)- phthalimidine of the formula XII Z I ,XI Z NH (Formula XI) with a (Q"') -,O (trialkyloxonium) salt provides 1- (X")-l-(X')-3-(OQ"')-5-(Z)-6-(Z')-ll-I-isoindole of Formula III. The preferred trialkyloxonium salt is triethyloxonium fluoborate [(C H O BF Those phthalimidines of Formula XI in which X and X are hydrogen are prepared, for example, by zinc and acetic acid reduction of the corresponding phthalimides.

Those phthalimidines of Formula XI in which X" is alkyl, phenyl or phenylalkyl are prepared, for example, from the corresponding 3-(Z')-4-(Z)-phenyl-(X")- ketoximes of the formula XII | z NOH z (Formula XII by treatment with carbon monoxide and hydrogen under pressure and catalysis by cobalt octacarbonyl. Those phthalimidines of Formula XI in which X" is benzyl are also prepared by catalytic hydrogenation of the corresponding phthalimidines of Formula XI in which X" and X, taken together, are benzylidene.

Those phthalimidines of Formula X1 in which X" and X, taken together, are benzylidene or benzylidene substituted in the benzene ring are the phthalimidines defined by Formula V and are prepared, for example, bycondensing the corresponding phthalic anhydrides with the corresponding a-(X)-acetic acids under sodium acetate catalysis and treating the resulting 3- (X -methylene )-5-(Z )-6-(Z)-phthalides successively with sodium hydroxide, hydrochloric acid and am monia.

The following examples illustrate specific embodiments of my invention without limiting the latter thereto.

EXAMPLE 1 EXAMPLE 2 Condensation of l-methyl-3-ethoxy-lI-I-isoindole (III: X"=CH,-,, X'=Z=Z=H, Q'=C I-I and B- (dimethylamino)ethyl-amine affords l-methyl-3-{[2- (dimethylamino )ethyl amino} l H-isoindole (I: X=CH X=Z=Z'=H, Y=NQQ', Q=CH CH N(CH Q'=I-I).

EXAMPLE 3 EXAMPLE 4 Condensation of l-isopropyl-3-ethoxy-lH-isoindole (III: X"=CH(CH X=kZ=I-I, Q"'=C H and B- (dimethylamino)-ethylamine affords l-isopropyl-3-{ [2-(dirnethylamino)ethyl]amino}-1I-I-isoindole (I: X=CH(CH X=Z=Z=H, Y=NQQ', Q=CH CH N(CH ,Q'=H).

EXAMPLE 5 EXAMPLE 6 EXAMPLE 7 In a manner similar to that of Example 6, condensation of 1-benzyl-3-ethoxy-lH-isoindole (Ill: X"=CH C 11 X=Z=Z=H, Q"'=C H (17.3 g.) and B- (dimethylamino)ethylamine and treatment of an ethanol (300 ml.) solution of the resulting gum with picric acid (30 g.) afforded l-benzyl-3-{[2- (dimethylamino )-ethyl lamino} 1 H-isoindole (I: X=CH C N(CH;,) O'=H)dipicrate (16.9 g., m.p. l96l97C.).

Treatment of l-benzyl3- [2- (dimethylamino )ethyl]amino} l H-isoindole with cyclohexanesulfamic acid afforded l-benzyl-3-{[2- (dimethylamino )ethyl Iamino} l H-isoindole tris(cyclohexone-sulfamate (m.p. l46-148C.).

EXAMPLE 8 EXAMPLE 9 In a manner similar to that of Example 1 condensation of l-benzylidene-B-ethoxy-ll-l-isoindole (III: X"+X=CHC H (FC H Z=Z=H) (24.9 g., m.p. l02105C.) and B-(dimethylamino)ethyl-amine (40 ml.) and treatment of the resulting product with hydrochloric acid afforded l-benzylidene-3- {[2- (dimethylamino )-ethyl]-amino} 1 H-isoindole (I: X+X H Y==NQQ', Q=CH CH N(CH Q=H, Z=Z'=H)dihydrochloride (16.0 g., 240-241C.).

EXAMPLE 10 A. A mixture of 2-benzylidenephthalimidine (V: X"'= C H Z==Z=H) (72 g.) and thionyl chloride (300 ml.) was heated under reflux (for 2 da. then stripped of excess thionyl chloride. The residue was digested with Skellysolve A (82.6 g., m.p. l22l23C.). Part (35 g.) of the digested residue was recrystallized from Skellysolve 1B and part (1 g.) of the recrystallizate was again recrystallized from Skellysolve B, affording l-(achlorobenzylidene)-3-chloro-lH-isoindole (VI: X"'= C H X"%l, Z=Z'=H) (0.7 g., m.p. 126128C.). B.

A mixture of l-(a-chlorobenzylidene)-3-chloro-1H- isoindole (32.8 g.), B(dimethylarnino)ethylamine (21.1 g.) and ether (350 ml.) was stirred at room temperature (for 1.5 hr.) and filtered. Evaporation of the ether from the filtrate gave a viscous oil (40.1 g.), an ethereal solution of which was treated with hydrochloric acid. Two recrystallizations of the resulting solid (34.0 g., m.p. 159-160C.) firomisopropyl alcohol afforded I 1-(a-chlorobenzy1idene)-3-{[Z-(dimethylamino)ethyl]amino}-lH-isoindole (I: X+X=CClC H Y=NQQ', Q==CH CH N(CH -;)2, Q=Z=Z'=H) dihydrochloride (12.0 g., m.p. 272-273C. with decomposition).

EXAMPLE 1 1 By substituting thionyl bromide for thionyl chloride in Step A of Example 10 and carrying the resulting 1- (a-bromobenzylidene )-3-bromol H-isoindole through STep B, l-(oz-bromobenzylidene )-3- {[2- (dimethylamino )ethyl ]amino} l H-isoindole (I: X+X'= Y=NQQ', Q=CH2CH2N(CH3 )2 Q=Z=Z'=H) dihydrochloride is obtained.

EXAMPLE 12 A mixture of l-benzylidene-B-ethoity-lH-isoindole (20.0 g.) and piperidine (40 ml.) was heated under reflux (for 14 hr.). The resulting mixture was digested with methanol and filtered. Recrystallization of the solid 18.3 g., m.p. l45l47C.) from Skellysolve B afforded l-benzylidene-3-piperi-dino-1H-isoindole (I: X+X'= H Z=Z'=H) (16.5 g., m.p. l45l47C.).

EXAMPLE 13 A mixture of 1-(p-chlorobenzylidene)-3-ethoxy-lH- isoindole (Ill: X+X%HC H Cl-p, Q"'=C H Z=Z'=H) (22.6 g., m.p. l02103C.) and piperidine (40 ml.) was heated under reflux overnight. The solid was washed with ether and dried, affording l-(pchlorobenzylidene)-3-piperidino-lI-l-isoindole (l: X+X= H.,Cl-p,

Z=Z'=H) (22.0 g., m.p. l74175C.).

EXAMPLE l4 Condensation of l-(p-hydroxybenzylidene)-3-ethoxy-lH-isoindole (Ill: X"+X'=CHC H OH-p, Q" '=C H Z=Z'=H) and piperidine affords l-(p-hydroxybenzylidene )-3-piperidinol l-l-isoindole (I: X+X'=CHC H O -P.

EXAMPLE 24 A mixture of 1-(oz-chlorobenzylidene)-3-chloro-1H- isoindole (22 g.), piperidine (13.6 g.) and ether (400 ml.) was stirred at room temperature (for 3 hr.). The mixture was filtered. The filtrate was dried and concentrated. Crystallization of the residue from Skellysolve A g ave l-(oz-chloro-benzylidene)-3-piperidino-lI-I-isoindole (I: X+X=CClC H Z=Z'=H) (17.6 g., m.p. 6263C.).

EXAMPLE A mixture of 1-benzylidene-3-ethoxy-lH-isoindole (50 g.), ammonium chloride (20 g.) and methanol (1000 ml.) was heated under reflux (for 2.5 da.). Evaporation of the methanol and recrystallization of the residue, first from ethanol and then from isopropyl alcohol, gave l-benzylidene-3-amino-lH-isoindole (I: X+X'= H Y=NQQ, Q=Q'=Z=Z=.H) hydrochloride (12.0 g., m.p. 256-257C. with decomposition).

EXAMPLE 26 Condensation of l-benzylidene-3-ethoxy-lI-l-isoindole and methylammonium chloride affords l-benzylidene-3-(methyl-amino 1 I-l-isoindole (I: X+X'= B 57 Q=CH3, hydrochloride.

EXAMPLE 27 Condensation of 1 -benzylidene-3-ethoxyl H-isoindole and isopropylammonium chloride affords lbenzylidene-3-( iso-propylamino l H-isoindole (I: X+X= H Y=NQQ, Q=CH(Cl-l Q'=Z- Z'=I-I) hydrochloride.

EXAMPLE 28 Condensation of 1-benzylidene-3-ethoxy-lH-isoindole and pentylammonium chloride affords l-benzy- A mixture of 3-ethoxy-1H-isoindole (16 g.) and benzylamine (15 g.) was heated (l30-135C. for 1% hr.). The excess benzylamine was distilled under vacuum. Recrystallization of the crystalline residue from Skellysolve B gave S-(benzylamino )-lH-isoindole (I: X=X'=Z=Z'=H, Y=NQQ, Q=CH C H Q=H) 1 1.0 g.,m.p. 1o4-105c.

EXAMPLE 3O Condensation of 3-ethoxy-lH-isoindole and 3-phen- EXAMPLE 31 Condensation of 3-ethoxylH-isoindole and pchloro-benzylamine afiords 3-(p-chlorobenzylamino)- lH-isoindole (l: X=X=Z=Z=H, Y=NOO. )=(H l-hCl-p, Q=H).

EXAMPLE 3 2 Condensation of 3-ethoxy-1H-isoindole and phydroxy-benzylamine affords 3-(p-hydroxybenzylamino)-lH-isoindole (I: X=X=Z=Z=H, Y=NQQ Q=CH C H OH-p, Q=H).

EXAMPLE 33 Condensation of 3-ethoxy-lH-isoindole and pmethoxy-benzylamine affords 3-(p-methoxybenzylamino)-lH-isoindole (I: X=X'=Z=Z=H, Y=NQQ' Q==CH C H OCH -p, Q=H).

EXAMPLE 34 A mixture of 3-ethoxy-1H-isoindole (9.0 g.), 3,4,5- trimethoxybenzylamine hydrochloride (13.0 g.) and methanol (150 ml.) was heated under reflux (for 5 hr.) under nitrogen. The mixture was stripped of solvent. Recrystallization of the residue (14.3 g., m.p. 227228 C.) from isopropyl alcohol gave 3-[(3,4,5-trimethoxybenzyl)amino]-lH-isoindole (I: X=X'=Z=Z'=H, Y=NQQ, Q=CH C H (OCH -3,4,5, Q=H) hydrochloride (8.1 g., m.p. 227-228C.).

EXAMPLE 35 Condensation of 3-ethoxy-1H-isoindole and p- (benzyloxy)benzylamine hydrochloride affords 3-[p- (benzyloxy)benzyl-amino]-lH-isoindole (I: X=X'= hydrochloride.

XAMPLE 36 Condensation of 3-ethoxy-lH-isoindole and p- (methyl-thio)benzylarnine hydrochloride affords 3-[p- (methylthio)benzyl-arnino]-lI-I-isoindole (I: X=X'= Z=Z'=NQQ', Q=CH C H SCH -p, Q=H) hydrochloride.

EXAMPLE 37 Condensation of 3-ethoxy-lH-isoindole and p- (dimethyl-amino)benzylamine hydrochloride affords 3-[p-(dimethylamino)-benzyl]-lH-isoindole (I: X=X'= Z=Z'=NQQI, QI=CH2CBH4N(CH3)2P, Q=H) hydrochloride.

EXAMPLE 38 A mixture of 3-ethoxy-lH-isoindole (8.0 g.) and p- EXAMPLE 39 Condensation of S-ethoxy-lI-I-isoindole and pnitrobenzyl-amine affords 3-(p-nitrobenzylamino)-1H- isoindole (I: X=X=Z=Z=I-I, Y=NQQ', Q=CI-I C H NO -p, Q'=I-I).

EXAMPLE 4O Condensation of 3-ethoxy-1I-i-isoindole and psulfamoyl-benzylamine affords 3-(p-sulfamoylbenzylamino)- l I-I-isoindole (I: X=X'=Z=Z'=H, Y=NQQ', Q=CH C H SO NH -p, Q'=H).

EXAMPLE 4] In a manner similar to that of Example 9, condensation of l-benzylidene-3-ethoxy-lH-isoindole (24.9 g.) and B-(diethylamino)ethylamine (30 ml.) and treatment of the resulting product with hydrochloric acid afforded 1-benzylidene-3- {[2-(diethylamino)ethyl ]a mino}-1I-I-isoindole (I: X+X'=CHC I-I Y=NQQ', Q=CH CH N(C I-I Q'=Z=Z=H) dihydrochloride l8.l g., m.p. 202204C. with decomposition).

EXAMPLE 42 Acylation of 1-benzylidene-3-amino-lH-isoindole hydrochloride with a mixture of acetic anhydride and pyridine gives l-benzylidene-3-acetamido-lI-I-isoindole (I: X+X'=CHC H Y=NQQ', Q==COCI-I;,, Q'=Z= Z'=H).

EXAMPLE 43 Acylation of 1-benzylidene-3-amino'lH-isoindole hydrochloride with a mixture of isobutyryl chloride and pyridine gives l-benzylidene-3-(isobutyrylamino)-1H- Acylation of l-benzylidene-3-amino-lH-isoindole hydrochloride with a mixture of benzoyl bromide and pyridine gives l-benzylidene-3-benzamido-lI-l-isoindole (I: X+X'=CHC5H,,, Y=NQQ', Q==COC I-I Q'=Z=Z=H).

EXAMPLE 45 EXAMPLE 46 Acylation of l-benzylidene-3-aminol H-isoindole hydrochloride with p-hydroxybenzoyl chloride gives 1- benzylidene-3-(p-hydroxybenzamido l H-isoindole (I: X+X= H Y=NQQ', Q=COC H OH-p, Q'=Z= Z'=H).

EXAMPLE 47 Acylation of l-benzylidene-B-amino-lI-I-isoindole hydrochloride with p-methoxybenzoyl chloride gives 1- benzylidene-3-(p-methoxybenzamido)- l I-I-isoindole (l: X+X=CI-IC H Y=NQQ', Q'=Z=Z=H).

EXAMPLE 48 Acylation of l-benzylidene-3-arnino- 1 I-I-isoindole i hydrochloride with 3,4,5-trimethoxybenzoyl chloride gives l-benzylidene-3-( 3 ,4,5-trimethoxybenzamido lI-I-isoindole (I: X+X'=CI-IC H Y=NQQ', Q=COC H (OCH -3,4,5, Q'=Z=Z=H).

EXAMPLE 49 Acylation of l-benzylidene-3-amino-lH-isoindole hydrochloride with p-(benzyloxy)benzoyl chloride gives l-benzylidene-3-[p(benzyloxy)benzamido]- I H- isoindole (I: X+X=CHC I-l Y=NQQ', Q=COC H OCH C H OCH P(Q'=Z=Z'=H).

EXAMPLE 50 Acylation of 1-benzylidene-3amino-lH-isoindole with p-(methylthio)benzoyl chloride gives l-benzylidene-3-[p-(methylthio)benzamido1-lH-isoindole (I: X+X'= Y=NQQ', Q=COC I-I SCH -p, Q'=Z= Z'=H).

EXAMPLE 51 Acylation of l-benzylidene-3-amino-lI-I-isoindole with p-(dimethylamino)benzoyl chloride gives 1- benzylidene-3-[p-(dirnethylamino)benzamido]-1H- isoindole (I: X+X=CHC H Y=NQQ', Q=COC H N(CI-I -p, Q'=Z=Z=H).

EXAMPLE 52 Acylation of 1-benzylidene-3-amino-II-I-isoindole with p-[2-(diethylarnino)ethoxy]benzoyl chloride gives l-benzylidene -3-{p-[Z-(diethylamino)ethoxy1benzamido}-lH-isoindole (I: X+X=CI-IC I-I Y=NQQ', Q=COC I-I OCH CI-I N(C H -p, Q'=Z=Z=H).

EXAMPLE 5 3 Acylation of l-benzylidene-3-amino-II-I-isoindole with p-nitrobenzoyl chloride gives 1-benzylidene-3-(pnitrobenzamido)-lH-isoindole (I: X+X=CI-IC I-I Y=NQQ Q=COC I-I NO -p, Q'=Z=Z=I-I EXAMPLE 54 Acylation of l-benzylidene-3-amino-lH-isoindole with p-sulfamoylbenzoyl chloride gives l-benzylidene- 3-(p-sulfamoylbenzamido)-lI-I-isoindole (I: X+X'= CI-IC H Y=NQQ', Q=COC H SO NI-I -p, Q'=Z= Z'=H).

EXAMPLE 5 5 Acylation of l-benzylidene-3-amino- 1 I-I-isoindole with B-phenylpropionyl chloride gives l-benzylidene-3- (B-phenylpropionamide)-lI-I-isoindole (I: X+X'= CI-IC I-I Y=NQQ', Q=COCH CH C5H5. Q'=Z= Z'=H).

EXAMPLE 56 Condensation of l-benzylidene-3-ethoxy-l H-isoindole and dimethylammonium chloride afford l-benzylidene-3-(dimethylamino)-lH-isoindole (I: X+X=I-I, Y=NQQ", Q=Q'=CH Z=Z=H) hydrochloride.

EXAMPLE 7 Condensation of l-benzylidene-3-ethoxy-lH-isoindole and dibutylammonium chloride affords l-benzy- A mixture of l-benzylidene-3-ethoxy-lH-isoindole (24.9 g.) and pyrrolidine (40 ml.) was heated at reflux overnight. The resulting solid was washed with ether, affording l-benzylidene-3-( l-pyrrolidinyD- 1 H-isoindole (I: X+X=CHC H Y=NQQ,

Z=Z=H) (19.7 g., m.p. 2l22 l 3C.).

EXAMPLE 59 EXAMPLE 60 Condensation of 1-methyl-3-ethoxyl H-isoindole and hydrazine affords l-methyl-3-hydrazino-lH-isoim dole (I: X=Cl-l X'=Z=Z'=l-I, Y=NQQ, Q=NH Q'=H).

EXAMPLE 61 Condensation of l-butyl-3-ethoxy-lH-isoindole and hydrazine affords l-butyl-3-hydrazino-lH-isoindole (I: X=(CH CH X'=Z=Z'=H, Y=NQQ, Q=NH Q'=H).

EXAMPLE 62 Condensation of l-phenyl-3-ethoxyl H-isoindole and hydrazine affords l-phenyl-3-hydrazino-lH-isoindole (I: X=C l-I X=#Z=H, Y=NQQ, Q=NH Q'=H).

EXAMPLE 63 Condensation of l-benzyl-3-ethoxy-lH-isoindole and hydrazine affords l-benzyl-3-hydrazino-1l-I-isoindole (I: X=C I-I CH X'=Z=Z'=l-l, Y=NQQ, Q=NH Q'=H).

EXAMPLE 64 EXAMPLE 65 EXAMPLE 66 EXAMPLE 67 Condensation of 3-ethoxy-5-methoxy-lH-isoindole (III: X"=X'= '=H, Q'=C H Z=CH 0) and hydrazine affords 3-hydrazino-5-methoxy- 1 H-isoindole (I: X=X'=Z'=H, Y=NQQ, Q=NH Q'=H, Z=CH O).

EXAMPLE 68 Condensation of 3-ethoxy-5 ,6-dimethoxy- 1 H-isoindole (III: X"=X'=H, Q"==C H Z=Z'=CH O) and hydrazine affords 3-hydrazino-5 ,G-dimethoxyl H- isoindole (I: X=X=H, Y=NQQ, Q=NH Q'=H, Z=Z'=CH O).

EXAMPLE 69 Condensation of 3-ethoxy-5 ,6-methylenedioxy-1H- isoindole (III: X"=X'=H, Q'=C H Z+Z=OCH O) and hydrazine affords 3-hydrazino-5,6-methylenedioxy-ll-l-isoindole (I: X=X=H, Y=NQQ, Q=NH Q'=H, Z+Z'= O).

EXAMPLE 70 In a manner similar to that of Example 59, condensation of 1-benzylidene-3-ethoxy-lH-isoindole (24.9 g.) and hydrazine (95 percent, 14.2 g.) gave a solid (18.7 g., m.p. l17l20C.), which was recrystallized from benzene, affording l-benzylidene-3-hydrazino 1 H- isoindole (I: X+X=CHC H Y=NQQ, Q=NH Q'=Z=Z=H) (9.0 g., m.p. l-l76C.).

EXAMPLE 7l Condensation of 3-ethoxy-lH-isoindole and hydroxylamine hydrochloride affords 3-hydroxylamino-lI-lisoindole (I: X=X'=Z=Z'=H, Y=NQQ, Q=OH, Q'=H) hydrochloride.

EXAMPLE 72 Condensation of 3-hydrazino-lH-isoindole and formaldehyde affords 3-(2-methylenehydrazino)-lH- isoindole (I: X=X'=Z=Z'=H, Y=NHN=CRR', R=R'= H).

EXAMPLE 73 Condensation of 3-hydrazino-lH-isoindole and acetaldehyde affords 3-(2-ethylidenehydrazino)-1H- isoindole (I: X=X'=Z=Z'=H, Y=NHN=CRR', R=CH R'=l-I).

EXAMPLE 74 Condensation of B-hydrazino-lH-isoindole and isobutyraldehyde affords 3-(2-isobutylidenehydrazino)- l H-isoindole (I: X=X=Z=Z=H,

Condensation of 3-hydrazino-lI-I-isoindole and pivaldehyde affords S-[Z-(tert-butylmethylene)hydrazino]-lI-I-isoindole (l: X=X=Z'-Z'= H, Y=NI-IN=CRR', R=C(CH R=I-I).

EXAMPLE 76 Condensation of 3-hydrazino-ll-l-isoindole and tiglaldehyde affords 3-[2-(2,3-dimethylallylidene)hydrazino]-ll-l-isoindole (I: X=X=Z=Z'=H, Y=NHN=CRR',R=C(Cl-l )=CHCl-I '=l-I).

EXAMPLE 77 Condensation of 3-hydrazino-1H-isoindole and cyclopentanecarboxaldehyde affords 3-[2-(cyclopentylmethylene)-hydrazino]-lH-isoindole (I: X=X'= Z=Z=Nl-IN=CRR,

EXAMPLE 7 8 Condensation of 3-hydrazino-lH-isoindole and 3- cyclohexenecarboxaldehyde affords 3-[2-(cyclohexenylmethylene)hydrazino]-lH-isoindole (l: X=X'= Z=Z'-NI-IN=CRR',

R=l-I).

EXAMPLE 79 Condensation of 3-hydrazino-lH-isoindole and benzaldehyde affords 3-(2-benzylidenehydrazino)-ll-I- isoindole (l: X=X'=Z=Z'=H, Y=NHN=CRR, R% H,, R=I-I).

EXAMPLE 80 Condensation of '3-hydrazino-ll-I-isoindole and aphenylpropionaldehyde affords 3-[2-(2-phenyl- EXAMPLE 8] Condensation of 3-hydrazino-lH-isoindole and amethyI-cinnamaldehyde affords 3-[2-(2-methyl-3- phenylallylidene)hydrazino]lI-l-isoindole (I: X=X'= Z=Z=Nl-IN=CRR', R=C(CH )=CHC H R=H).

EXAMPLE 82 Condensation of 3-hydrazino-Il-I-isoindole and pbromobenzaldehyde affords 3-[2-(p-bromobenzylidene)hydrazino]-lI-I-isoindole (I: X=X'=Z=Z=H, Y=NHN=CRR, R=C H Br-p, R=l-I).

EXAMPLE 83 Condensation of S-hydrazino-lH-isoindole and mhydroxybenzaldehyde affords 3-[2-(m-hydroxybenzylidene)hydrazino]-ll-I-isoindole (I: X=X=Z=Z=l-I, Y=NHN=CRR, R=C H OH-m, R=H).

EXAMPLE 84 Condensation of 3-hydrazino-1H-isoindole and ptolualdehyde affords 3-[2-(p-methylbenzylidene)hydrazino]-ll-I-isoindole (I: X=X'=Z=Z=l-l, Y=NHN=CRR', R=C H CH -p, R=H).

EXAMPLE 85 Condensation of 3-hydrazino4H-isoindole and syringaldehyde affords 3-[2-(3,5-dimethoxy-4-hydroxybenzylidene)hydrazino]-ll-I-isoindole (I: X=X'= Z=Z=NHN=CRR' R=C H OI-I-4-(OCH -3,5, R=l-I).

EXAMPLE 86 Condensation of 3-hydrazino-lH-isoindole and p- (ethylthio )benzaldehyde affords 3- {2- [p- (ethylthio)benzy1idene1hydrazino 1 I-I-isoindole (I: X=X=Z=Z'=I-I, Y=NHN=CRR, R=C H SC H -p, R=I-I).

EXAMPLE 87 Condensation of 3-hydrazino-lH-isoindole and p- (dimethylamino)benzaldehyde affords 3- {2- [p- (dimethylamino)benzylidene1hydrazine} 1H isoin dole (I: X=X'=Z=Z=I-I, Y=NHN=CRR', R=C H N(CH -p, R=H).

EXAMPLE 88 Condensation of 3-hydrazino-IH-isoindole and p-[2- (diethylamino) ethoxy]benzaldehyde affords 3-( 2-{p- [Z-(diethyl-amino)ethoxy]benzylidene}hydrazino)- Condensation of 3-hydrazino-lH-isoindole and .pnitrobenzaldehyde affords 3-[2-(p-nitrobenzylidene)hydrazino]-ll-l-isoiridole I: X=X=Z=Z=l-I, Y=NHNRRZ R=C H NO -p, R=I-I).

EXAMPLE 90 Condensation of 3-hydrazino-lH-isoindole and psulfamoylbenzaldehyde affords 3-[2-(p-sulfamoylbenzylidene)-hydrazino]-lH-isoindole (I: I X=X'= Z=Z'=Nl-IN=CRR, R=C l-I S0 NI-I p, R=H).

EXAMPLE 91 EXAMPLE 92 Condensation of 3-hydrazino-lI-I-isoindole and methyl isopropyl ketone affords 3-[2-(l,2-dimethyl- EXAMPLE 9 3 Condensation of 3-hydrazino-lH-isoindole and cyclohexanone affords 3-(2-cycloxylidenehydrazino)-l Condensation of l-methyl 3 -hydrazinol H-isoindole and acetone affords 1-methyl-3-(2-isopropylidenehydrazino)-lH-isoindole (I: X=CI-I X'=Z= Z'=I-I, Y=NHN=CRR, R=R=CH EXAMPLE 95 Condensation of 1-butyl-3-hydrazino-lH-isoindole and acetone affords l -butyl-3-( 2-isopropylidenehydrazino l I-I-isoindole (I: X=(CI-I CH X'=Z=Z'=H, Y=NHN=CRR', R=R'=CH EXAMPLE 96 Condensation of 1-phenyl-3 hydrazino-lH-isoindole and acetone affords l-phenyl-3-( 2-isopropylidenehydrazino)-lI-I-isoindole (I: X=C H X'=Z= Z'=H, Y=NHN=CRR, R=R=CH EXAMPLE 97 Condensation of l-benzyl-3-hydrazinol H-isoindole and acetone affords l-benzyl-3-( 2-isopropylidenehydrazino)-lI-I-isoindole (I: X=C I-I CH X'=Z= Z'=I-I, Y=NHN=CRR', R=R'=CH EXAMPLE 98 Condensation of 3-hydrazino-6-methyl- 1 H-isoindole and acetone affords 3-(2-isopropylidenehydrazino)-5- methyl-lH-isoindole (I: X=X'= '=I-I, Y=NHN=CRR', R=R'=Z#JH EXAMPLE 99 Condensation of 3-hydrazino-5-chlorol H-isoindole and acetone affords 3-(2-isopropylidenehydrazino)-6- chloro-lH-isoindole (I: X=X=Z=H, Y=NHN=CRR, R=R=CH Z'=Cl).

EXAMPLE I O0 Condensation of 3-hydrazino-5-hydroxy-lH-isoindole and acetone affords 3-( 2-isopropylidenehydrazino )-6-hydroxy- 1 I-I-isoindole (I: X=X'= kI-I, Y=NHN=CRR, R=R=CH Z'=HO).

EXAMPLE lOl Condensation of 3-hydrazino-5-methoxylH-isoindole and acetone affords 3-( 2-isopropylidenehydrazino)-6-methoxy-lI-I-isoindole (I: X=X'= Z=H, Y=NHN=CRR, R=R=CH Z'=CH O).

EXAMPLE 102 Condensation of 3-hydrazino-5,6-dimethoxy-1H- isoindole and acetone affords 3-(2-isopropylidenehydrazino)-5,o-dimethoxy-1H-isoindole (I:

EXAMPLE 103 Condensation of 3-hydrazino-5,6-methylenedioxy-l I-I-isoindole and acetone affords 3-(2-isopropylidenehydrazino)-5 ,6-methylenedioxy- 1 I-I-isoindole (I: X=X'=H, Y=NI-IN=CRR', R=R=CI-I Z+Z'= OCI-I O).

Iclaim:

1. 1-(X)-l-(X')-3-(Y)-5-(Z)-6-(Z)-lH-Isoindole of the formula wherein X and X, when taken together, are benzylidene, a-

chlorobenzylidene or a-bromobenzylidene;

wherein Q, when taken alone, is hydrogen; alkyl of one to six carbon atoms; phenylalkyl of seven to ten carbon atoms; (CH ),,-T, wherein n is two or three and T is dialkylamino, wherein alkyl of dialkylamino is atertiary alkyl of one to four carbon atoms; alkanoyl of one to six carbon atoms; benzoyl; phenylalkanoyl of eight to eleven carbon atoms; amino or hydroxy;

Q, when taken alone, is hydrogen or atertiary alkyl of one to four carbon atoms;

Q and Q, when taken together with N, are l-azacycloalkyl of five to seven ring atoms and four to ten carbon atoms;

R, when taken alone, is hydrogen, alkyl of one to six carbon atoms, alkenyl of two to six carbon atoms, cycloalkyl of three to seven ring atoms and three to ten carbon atoms, cycloalkenyl of five to seven ring atoms and five to ten carbon atoms, phenyl, phenylalkyl of seven to ten carbon atoms or phenylalkenyl of eight to ten carbon atoms;

R, when taken alone, is hydrogen or atertiary alkyl of one to four carbon atoms;

R and R, when taken together with C, are cycloalkylidene of five to seven ring atoms and five to ten carbon atoms;

Z and Z, when taken alone are the same or different and are hydrogen, atertiary alkyl of one to four carbon atoms, halo, hydroxy or atertiary alkoxy of one to four carbon 'atoms;

Z and Z, when taken together, are methylenedioxy;

and wherein,

when X and X are benzylidene, a-chlorobenzylidene or a-bromo-benzylidene, Q is phenylalkyl of seven to ten carbon atoms or benzoyl and/or R is phenyl, the benzene ring thereof can be substituted by one to three members selected from the group consisting of halo, hydroxy, atertiary alkyl of one to four carbon atoms, atertiary alkoxy of one to four carbon atoms and phenylalkoxy of seven to ten carbon atoms or by a member selected from the group consisting of atertiary alkylthio of one to four carbon atoms, dialkylamino and B-dialkylaminoethoxy, wherein alkyl of dialkylamino is atertiary alkyl of one to four carbon atoms, nitro and sulfamoyl; and acid addition salts thereof.

2. l-(X)-1-(X')-3-(Y)-5-(Z)-6-(Z')-lH-lsoindole wherein X and X, when taken together, are benzylidene and Y is NQQ', wherein Q is hydrogen according to claim 1.

3. l-(X)-l-(X)-3 (Y)-5-(Z)-6-(Z')-lH-lsoindole wherein X and X, when taken together, are benzylidene and Y is NQQ', wherein Q is (CH ),,-T, wherein n is two or three and T is dialkylamino, wherein alkyl of dialkylamino is atertiary alkyl of one to four carbon atoms, according to claim 1.

4. 1-(X)-l-(X)-3-(Y)-5-(Z)-6-(Z')-lH-lsoindole wherein X and X, when taken together, are benzylidene and Y is NQQ', wherein Q is benzoyl, according to claim 1.

5. l-(X)-l-(X)-3-(Y)-5-(Z)-6-(Z)-lHlsoindole wherein X and X, when taken together, are benzylidene and Y is NQQ', wherein Q is amino, according to claim 1.

6. l-(X)-l-(X')-3-(Y)-5-(Z)-6-(Z)-lH-lsoindole wherein X and X, when taken together, are benzylidene and Y is NQQ', wherein Q and Q, when taken together with N, are l-azacycloalkyl of five to seven ring atoms and four to ten carbon atoms, according to claim 1.

7. l-(X)-l-(X)-3-(Y)-5-(Z)-6-(Z')-lH-Isoindole wherein X and X, when taken together, are

achlorobenzylidene and Y is NQQ', wherein Q is (CH ),,-T, wherein n is two or three and T is dialkylamino, wherein alkyl of dialkylamino is atertiary alkyl of one to four carbon atoms, according to claim 1.

8. l-(X)-1-(X )-3-(Y)-5-(Z)-6-(Z)-1H-Isoindole wherein X and X, when taken together, are achlorobenzylidene and Y is NQQ', wherein Q and Q, when taken together with N, are l-azacycloalkyl of five to seven ring atoms and four to ten carbon atoms, according to claim 1.

9. I-Benzylidene-3-{[2-(dimethylamino)ethyl1a mino}- l H-isoindole according to claim 3.

l0. l-Benzylidene-3-piperidino-1 H-isoindole cording to claim 3.

1 1. 1-(p-Chlorobenzylidene)-3-piperidinol H-isoindole according to claim 6.

l2. l-(p-Methoxybenzylidene )-3-piperidino-l H- isoindole according to claim 6.

l3. l-[p-( Benzyloxy)benzylidene]-3-piperidinol H- isoindole according to claim 6.

14. l-Benzylidene-3-amino-lH-isoindole according to claim 2.

l5. l-Benzylidene-3-{[2-(diethylamino)ethyHamino} l H-isoindole according to claim 3.

16. l-Benzylidene-3-(l-pyrrolidinyl)-lH-isoindole according to claim 6.

17. l-Benzylidene-3-hydrazino-1H-isoindole according to claim 5.

18. l-(a-Chlorobenzylidene)-3- {[2- (dimethylamino)ethyl ]-amino} l H-isoindole accordingto claim 7. I I

9. 1 -(a-Chlorobenzylidene )-3-p1perid1nol l-l-isomdole according to claim 8.

20. 1-Benzylidene-3-(p-chlorobenzamido)-1 H-isoindole according to claim 4.

Im'cntor( Guy D. Diana.

error appears in the above-identified fiatcnt shown below:

It is'ccrtificd' that and that said Letters Patent are hereby corrected as T Claim 10, "according to claim 3" should read --according to claim. 6.

Signed anfi seamed this 20th day of November 1973.

(SEAL) Attestz RENE D. TEG'I'MEYER EDWARD M.FLEI'CHER,J'R.. Attcstinq Officer Acting Commissioner of Patents 

2. 1-(X)-1-(X'')-3-(Y)-5-(Z)-6-(Z'')-1H-Isoindole wherein X and X'', when taken together, are benzylidene and Y is NQQ'', wherein Q is hydrogen according to claim
 1. 3. 1-(X)-1-(X'')-3-(Y)-5-(Z)-6-(Z'')-1H-Isoindole wherein X and X'', when taken together, are benzylidene and Y is NQQ'', wherein Q is (CH2)n-T, wherein n is two or three and T is dialkylamino, wherein alkyl of dialkylamino is atertiary alkyl of one to four carbon atoms, according to claim
 1. 4. 1-(X)-1-(X'')-3-(Y)-5-(Z)-6-(Z'')-1H-Isoindole wherein X and X'', when taken together, are benzylidene and Y is NQQ'', wherein Q is benzoyl, according to claim
 1. 5. 1-(X)-1-(X'')-3-(Y)-5-(Z)-6-(Z'')-1H-Isoindole wherein X and X'', when taken together, are benzylidene and Y is NQQ'', wherein Q is amino, according to claim
 1. 6. 1-(X)-1-(X'')-3-(Y)-5-(Z)-6-(Z'')-1H-Isoindole wherein X and X'', when taken together, are benzylidene and Y is NQQ'', wherein Q and Q'', when taken together with N, are 1-azacycloalkyl of five to seven ring atoms and four to ten carbon atoms, according to claim
 1. 7. 1-(X)-1-(X'')-3-(Y)-5-(Z)-6-(Z'')-1H-Isoindole wherein X and X'', when taken together, are Alpha chlorobenzylidene and Y is NQQ'', wherein Q is (CH2)n-T, wherein n is two or three and T is dialkylamino, wherein alkyl of dialkylamino is atertiary alkyl of one to four carbon atoms, according to claim
 1. 8. 1-(X)-1-(X'')-3-(Y)-5-(Z)-6-(Z'')-1H-Isoindole wherein X and X'', when taken together, are Alpha -chlorobenzylidene and Y is NQQ'', wherein Q and Q'', when taken together with N, are 1-azacycloalkyl of five to seven ring atoms and four to ten carbon atoms, according to claim
 1. 9. 1-Benzylidene-3-((2-(dimethylamino)ethyl)amino)-1H-isoindole according to claim
 3. 10. 1-Benzylidene-3-piperidino-1H-isoindole according to claim
 3. 11. 1-(p-Chlorobenzylidene)-3-piperidino-1H-isoindole according to claim
 6. 12. 1-(p-Methoxybenzylidene)-3-piperidino-1H-isoindole according to claim
 6. 13. 1-(p-(Benzyloxy)benzylidene)-3-piperidino-1H-isoindole according to claim
 6. 14. 1-Benzylidene-3-amino-1H-isoindole according to claim
 2. 15. 1-Benzylidene-3-((2-(diethylamino)ethyl)amino)-1H-isoindole according to claim
 3. 16. 1-Benzylidene-3-(1-pyrrolidinyl)-1H-isoindole according to claim
 6. 17. 1-Benzylidene-3-hydrazino-1H-isoindole according to claim
 5. 18. 1-( Alpha -Chlorobenzylidene)-3-((2-(dimethylamino)ethyl)-amino)-1H-isoindole according to claim
 7. 19. 1-( Alpha -Chlorobenzylidene)-3-piperidino-1H-isoindole according to claim
 8. 20. 1-Benzylidene-3-(p-chlorobenzamido)-1H-isoindole according to claim
 4. 